Ramipril Mas Telmisartan

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n engl j med 358;15 www.nejm.org april 10, 2008 1547

Thenew englandjournalofmedicineestablished in 1812 april 10, 2008 vol. 358 no. 15

Telmisartan, Ramipril, or Both in Patients at High Riskfor Vascular Events

The ONTARGET Investigators*

A b s t ra c t

The members of the writing committee(Salim Yusuf, D.Phil., Koon K. Teo, Ph.D.,Janice Pogue, M.Sc., Leanne Dyal, M.Sc.,and Ingrid Copland, Population HealthResearch Institute, McMaster Universityand Hamilton Health Sciences, Hamil-ton, ON, Canada; Helmut Schumacher,Ph.D., Boehringer Ingelheim, Ingelheim,Germany; Gilles Dagenais, M.D., LavalUniversity Heart and Lung Institute, La-val Hospital, Quebec, QC, Canada; PeterSleight, D.M., Oxford University, Oxford,United Kingdom; and Craig Anderson,Ph.D., George Institute for InternationalHealth, University of Sydney, Sydney) as-

sume responsibility for the overall con-tent and integrity of the article. Addressreprint requests to Dr. Yusuf at the Popu-lation Health Research Institute, HamiltonHealth Sciences and McMaster University,237 Barton St. East, Hamilton, ON L8L 2X2,Canada, or at [email protected].

*The Ongoing Telmisartan Alone and inCombination with Ramipril Global End-point Trial (ONTARGET) investigatorsare listed in the Appendix.

This article (10.1056/NEJMoa0801317) waspublished at www.nejm.org on March 31,2008.

N Engl J Med 2008;358:1547-59.Copyright 2008 Massachusetts Medical Society.

Background

In patients who have vascular disease or high-risk diabetes without heart failure,angiotensin-convertingenzyme (ACE) inhibitors reduce mortality and morbidityfrom cardiovascular causes, but the role of angiotensin-receptor blockers (ARBs)in such patients is unknown. We compared the ACE inhibitor ramipril, the ARBtelmisartan, and the combination of the two drugs in patients with vascular diseaseor high-risk diabetes.

Methods

After a 3-week, single-blind run-in period, patients underwent double-blind random-ization, with 8576 assigned to receive 10 mg of ramipril per day, 8542 assigned toreceive 80 mg of telmisartan per day, and 8502 assigned to receive both drugs (com-bination therapy). The primary composite outcome was death from cardiovascularcauses, myocardial infarction, stroke, or hospitalization for heart failure.

Results

Mean blood pressure was lower in both the telmisartan group (a 0.9/0.6 mm Hggreater reduction) and the combination-therapy group (a 2.4/1.4 mm Hg greaterreduction) than in the ramipril group. At a median follow-up of 56 months, the pri-mary outcome had occurred in 1412 patients in the ramipril group (16.5%), ascompared with 1423 patients in the telmisartan group (16.7%; relative risk, 1.01;95% confidence interval [CI], 0.94 to 1.09). As compared with the ramipril group,the telmisartan group had lower rates of cough (1.1% vs. 4.2%, P


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T h e n e w e n g l a n d j o u r n a l o f medicine

n engl j med 358;15 www.nejm.org april 10, 20081548

Randomized, controlled trials in-volving about 150,000 patients have con-vincingly demonstrated that angiotensin-convertingenzyme (ACE) inhibitors reduce ratesof death, myocardial infarction, stroke, and heartfailure among patients with heart failure,1 leftventricular dysfunction,2-4previous vascular dis-

ease alone,5-7or high-risk diabetes.8ACE inhibi-tors do not block the production of all angioten-sin II, so direct receptor blockade might be moreeffective. ACE inhibitors reduce bradykinin degra-dation, which enhances vasodilatation, but in-crease the rates of angioedema and cough. In pa-tients with heart failure, angiotensin II levels mayincrease and symptoms worsen, despite the useof ACE inhibitors.9The use of an angiotensin-receptor blocker (ARB), as compared with placebo,reduced the rate of death or hospitalization forheart failure in patients with a low ejection frac-

tion and heart failure who either could not toler-ate an ACE inhibitor10or were already receivingone.11,12As compared with beta-blockers, ARBsalso reduced vascular events in high-risk patientswith hypertension and left ventricular hypertro-phy.13 Nevertheless, in other high-risk popula-tions, the role of ARBs as an alternative or in ad-dition to ACE inhibitors to prevent cardiovascularoutcomes is not known.

We evaluated whether the ARB telmisartanwas not inferior to the ACE inhibitor ramipriland whether a combination of the two drugs wassuperior to ramipril alone as a treatment to pre-vent vascular events in high-risk patients who hadcardiovascular disease or diabetes mellitus but didnot have heart failure. We used a dose of ramiprilthat had previously been shown to be effectivefor this outcome.

Methods

Study Design

The design of the study has been described previ-

ously.14

We enrolled patients with coronary, periph-eral, or cerebrovascular disease or diabetes withend-organ damage. Patients who could not toler-ate ACE inhibitors were randomly assigned toreceive either telmisartan or placebo in a paralleltrial.14Detailed eligibility criteria have also beendescribed previously14 (for details, see the Sup-plementary Appendix, available with the full textof this article at www.nejm.org). The primary ob-jectives of our study were to determine the effec-tiveness of 80 mg of telmisartan daily, as com-

pared with 10 mg of ramipril daily. If thenoninferiority of telmisartan was demonstrated,we would test the superiority of telmisartan overramipril. We would also determine whether thecombination of the two drugs was more effectivethan ramipril alone in reducing the compositeoutcome of death from cardiovascular causes,

myocardial infarction, stroke, or hospitalizationfor heart failure.

The main secondary outcome was a compos-ite of death from cardiovascular causes, myocar-dial infarction, or stroke, which was the primaryoutcome in the Heart Outcomes Prevention Evalu-ation (HOPE) trial.5Other secondary outcomeswere new heart failure, diabetes mellitus, atrialfibrillation, dementia or cognitive decline, ne-phropathy, and revascularization procedures.Other outcomes were death from any cause orfrom noncardiovascular causes, angina, transient

ischemic attack, development of left ventricularhypertrophy, microvascular complications of di-abetes, changes in blood pressure or in the ankle-to-arm ratio of blood pressure, and new cancers.

National coordinators and clinical monitorssupervised the recruitment of patients at 733 cen-ters in 40 countries. The trial was coordinated anddata were gathered and analyzed by the Popula-tion Health Research Institute at McMaster Uni-versity and Hamilton Health Sciences, with coor-dinating suboffices at Oxford University and theUniversity of Auckland. The steering committeedesigned and oversaw the trial. An operationscommittee, with representatives from the threecoordinating centers and the sponsor (BoehringerIngelheim), met regularly to evaluate progress.

All main study outcomes (death according toany cause, myocardial infarction, stroke, and hos-pitalization for heart failure) were adjudicated bya central committee whose members were un-aware of study-group assignments, with the useof standard criteria.14All serious adverse eventswere reviewed by an independent data and safety

monitoring board.The initial draft of the manuscript was writ-ten by Dr. Yusuf and the writing committee, whovouch for the data, with input from the steeringcommittee. The protocol was approved by regu-latory authorities and the ethics review commit-tee at each participating institution.

Run-in Period and Randomization

After written informed consent was obtained, pa-tients entered a single-blind run-in period in which

Copyright 2008 Massachusetts Medical Society. All rights reserved.Downloaded from www.nejm.org on April 2, 2008 . For personal use only. No other uses without permission.


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Telmisartan, Ramipril, or Both in High-Risk Vascular Disease


they received 2.5 mg of ramipril once daily for3 days, followed by 40 mg of telmisartan and 2.5mg of ramipril once daily for 7 days and then 5 mgof ramipril plus 40 mg of telmisartan for 11 to18 days. Of the 29,019 patients who entered therun-in period, 3399 (11.7%) were excluded fromthe study: 1123 (3.9%) had poor compliance, 597

(2.1%) withdrew from the study, 492 (1.7%) hadsymptomatic hypotension, 223 (0.8%) had an el-evated potassium level, 64 (0.2%) had an elevatedcreatinine level, 872 (3.0%) had other reasons forexclusion, and 27 (0.1%) died.

A total of 25,620 patients underwent random-ization and were stratified according to site withthe use of permuted blocks through a central auto-mated telephone service. For the first 2 weeks afterrandomization, 8542 patients were assigned toreceive 80 mg of telmisartan once daily, 8576 wereassigned to receive 5 mg of ramipril once daily,

and 8502 were assigned to receive a combinationof the two drugs (combination therapy). After2 weeks, the dose of ramipril was increased to10 mg per day. Follow-up visits occurred at6 weeks, at 6 months, and then every 6 monthsuntil the last scheduled visit.

Interim Analysis and Data Monitoring

An independent data and safety monitoring boardof cardiologists, statisticians, and clinical-trial ex-perts met twice yearly; three formal interim anal-yses were conducted when 25%, 50%, and 75%of the events accrued. A modified HaybittlePetoapproach15guided decisions (i.e., a boundary of4 SD in the first half of the trial and 3 SD in thesecond half for efficacy; for safety, if boundariesof 3 SD and 2 SD, respectively, were crossed in asecond analysis 4 to 6 months later, it would trig-ger consideration of stopping).

Statistical Analysis

The number of patients was based on the rateof death from cardiovascular causes, myocardi-

al infarction, stroke, or hospitalization for heartfailure associated with ramipril in the HOPE tri-al, in which the KaplanMeier estimate for theprimary outcome was 0.0397 per year. A determi-nation of noninferiority required a hazard ratiofor telmisartan as compared with ramipril thatwas below a predefined margin, with most oframiprils effect, as compared with placebo, re-tained by telmisartan.

The margin was determined by the results ofthe HOPE trial, in which the hazard ratio with

10 mg of ramipril, as compared with placebo,was 0.775 for a composite outcome of deathfrom cardiovascular causes, myocardial infarc-tion, stroke, or hospitalization for heart failure;this was similar to the hazard ratios in otherstudies comparing ACE inhibitors with place-bo.6,7We chose the 40th percentile (0.794) as a

more robust reference to describe the effect oframipril. The relative risk was translated into anexcess risk for placebo as compared with ramiprilof 1.26. Thus, a margin of 1.13 ensured that telmi-sartan retained at least half the effect of ramipril,if the upper limit of the one-sided 97.5% confi-dence interval for the hazard ratio was less thanthis value. We also evaluated whether the com-bination of telmisartan plus ramipril was supe-rior to ramipril alone.

We tested both hypotheses using group se-quential tests with a one-sided type I error of

0.025, with three planned interim analyses. If oneof the two comparisons did not reject the nullhypothesis, the other comparison needed an alphaof 0.0125. The original planned sample size of7800 patients who were followed for a mean of4.5 years provided a power of 93% for the supe-riority hypothesis, if the hazard ratio was 0.87.For noninferiority, the expected power was 89%,for a hazard ratio of 1.00.

The primary analysis used a time-to-event ap-proach, counting the f irst occurrence of any com-ponent of the composite outcome, and includedall randomized patients. All reported P values(other than for noninferiority) are two-sided. Con-sistency of treatment effects in prespecified sub-groups was explored by the Cox regression model,with tests for interaction.16,17We performed asensitivity analysis according to the protocol bycensoring data from patients who took the studydrugs for less than 50% of the study period.

Results

Characteristics of the PatientsCharacteristics of the 25,620 patients who under-went randomization were similar in the threestudy groups (Table 1); 27% were women, 85%had cardiovascular disease, 69% had hyperten-sion, and 38% had diabetes. A high proportion ofpatients had previously received proven therapies:statins (61.6% at baseline, increasing to 70.6% bythe end of the study), antiplatelet therapy (80.9%and 77.5%, respectively), beta-blockers (56.9% and56.9%), and diuretics (28.0% and 32.5%).



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Table 1.Baseline Characteristics of the Patients.*

CharacteristicRamipril

(N = 8576)Telmisartan(N = 8542)

Combination Therapy(N = 8502)

Age yr 66.47.2 66.47.1 66.57.3

Blood pressure mm Hg 141.817.4/82.110.4 141.717.2/82.110.4 141.917.6/82.110.4

Heart rate beats/min 67.912.2 68.012.3 67.712.2

Body-mass index 28.14.5 28.14.6 28.04.5

Cholesterol mmol/liter

Total 4.91.1 4.91.1 5.01.2

LDL 2.91.0 2.91.0 2.91.0

HDL 1.30.4 1.30.4 1.30.4

Triglycerides mmol/liter 1.71.1 1.71.l 1.71.1

Glucose mmol/liter 6.72.6 6.72.5 6.72.6

Creatinine mol/liter 93.522.8 93.822.8 93.822.8

Potassium mmol/liter 4.40.4 4.40.4 4.40.5

Female sex no. (%) 2331 (27.2) 2250 (26.3) 2250 (26.5)

Ethnic group no. (%)

Asian 1182 (13.8) 1172 (13.7) 1167 (13.7)

Arab 102 (1.2) 106 (1.2) 106 (1.2)

African 206 (2.4) 215 (2.5) 208 (2.4)

European 6273 (73.1) 6213 (72.7) 6222 (73.2)

Native or aboriginal 747 (8.7) 756 (8.9) 728 (8.6)

Other ethnic group 64 (0.7) 77 (0.9) 69 (0.8)

Missing data 2 (


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Follow-up and Adherence

A total of 25,577 patients (99.8%) were followeduntil a primary event occurred or until the end ofthe study (median, 56 months). Among patientsin the ramipril group, 92.2% were taking an ACEinhibitor and 1.0% were taking an ARB at 1 year,with respective proportions of 89.4% and 1.8% at2 years, 87.5% and 2.0% at 3 years, 86.6% and2.4% at 4 years, and 84.7% and 3.3% at the endof the study. Among patients in the telmisartangroup, 93.9% were taking an ARB and 2.6% weretaking an ACE inhibitor at 1 year, with respectiveproportions of 91.2% and 4.2% at 2 years, 89.3%and 4.6% at 3 years, 87.7% and 5.0% at 4 years,and 85.6% and 6.4% at the end of the study.Among patients in the combination-therapy group,85.5% received both drugs, 2.8% received an ACEinhibitor only, and 3.5% received an ARB only at1 year; the respective proportions were 81.5%,4.2%, and 4.8% at 2 years; 78.7%, 4.5%, and 5.4%at 3 years; 76.8%, 4.7%, and 5.7% at 4 years; and73.6%, 6.0%, and 6.4% at the end of the study.

The proportion of patients receiving the fulldose of ramipril at 2 years was 81.7% in theramipril group and 75.3% in the combination-therapy group. The proportion of patients receiv-ing the full dose of telmisartan at 2 years was88.6% in the telmisartan group and 84.3% inthe combination-therapy group. The study drugwas discontinued by 2029 patients (23.7%) in theramipril group and 1796 (21.0%) in the telmisar-tan group. In the combination-therapy group, 1929

patients (22.7%) discontinued both drugs, and anadditional 566 (6.7%) stopped taking one drug.

The most important reasons for permanentdiscontinuation of a study drug are summarizedin Table 2. More patients discontinued ramipril(either as monotherapy or with telmisartan) be-cause of cough or angioedema than discontinuedtelmisartan alone. In the combination-therapygroup, an increased number of patients stoppedtaking a study drug because of hypotensive symp-toms, syncope, diarrhea, or renal impairment, ascompared with the ramipril groups.

Blood Pressure, Potassium, and Creatinine

Before the run-in period, the mean blood pres-sure was 141.8/82.1 mm Hg. At 6 weeks, the meanblood pressure was reduced by 6.4/4.3 mm Hg inthe ramipril group, by 7.4/5.0 mm Hg in the tel-misartan group, and by 9.8/6.3 mm Hg in thecombination-therapy group. Patients in the telmi-sartan group and the combination-therapy groupcontinued to have slightly lower blood-pressure

levels throughout the study period (average reduc-tions, 0.9/0.6 mm Hg and 2.4/1.4 mm Hg, respec-tively) than did patients in the ramipril group. Thenumbers of patients who had a doubling of thecreatinine level were similar in the three groups(159 in the ramipril group, 170 in the telmisartangroup, and 180 in the combination-therapy group).The numbers of patients who had an increase inthe potassium level of more than 5.5 mmol perliter were similar in the ramipril group (283 pa-

Table 1.(Continued.)

CharacteristicRamipril



Medication no. (%)

Statin 5234 (61.0) 5294 (62.0) 5255 (61.8)

Beta-blocker 4847 (56.5) 4860 (56.9) 4876 (57.4)

Aspirin 6473 (75.5) 6469 (75.7) 6461 (76.0)

Clopidogrel or ticlopidine 927 (10.8) 966 (11.3) 931 (11.0)

Antiplatelet agent 6903 (80.5) 6926 (81.1) 6898 (81.1)

Diuretic 2454 (28.6) 2359 (27.6) 2351 (27.7)

Calcium-channel blocker 2821 (32.9) 2787 (32.6) 2864 (33.7)

* Plusminus values are means SD. HDL denotes high-density lipoprotein, and LDL low-density lipoprotein. A total of 13,386 patients had a systolic blood pressure of more than 140 mm Hg. Body-mass index is the weight in kilograms divided by the square of the height in meters. Ethnic group was self-reported. The percentage is based on 21,074 patients who underwent baseline urinary analysis: 7073 patients in the ramipril

group, 7013 patients in the telmisartan group, and 6988 patients in the combination-therapy group.



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tients) and the telmisartan group (287 patients),but the number was significantly higher in thecombination-therapy group (480 patients, P


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P


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benefits of ARBs are being evaluated in threeother placebo-controlled trials that are expectedto be completed in 2008.14,18,19

Our results parallel the findings of theValsartan in Acute Myocardial Infarction Trial(VALIANT),20which established the noninferior-ity of valsartan, as compared with captopril, in

patients with left ventricular dysfunction or heartfailure after myocardial infarction. The upperboundaries of the confidence intervals and thenoninferiority margins were almost identical inthe two studies, even though they enrolled differ-ent patient populations. The side effects in ourstudy were similar to those in the VALIANT study,

Table 3.Incidence of the Primary Outcome, Its Components, and Death from Any Cause.

OutcomeRamipril



Telmisartan vs.Ramipril

Combination Therapyvs. Ramipril

number (percent) risk ratio (95% CI)

Death from cardiovascular causes, myo-cardial infarction, stroke, or hos-

pitalization for heart failure*

1412 (16.5) 1423 (16.7) 1386 (16.3) 1.01 (0.941.09) 0.99 (0.921.07)

Death from cardiovascular causes, myo-cardial infarction, or stroke

1210 (14.1) 1190 (13.9) 1200 (14.1) 0.99 (0.911.07) 1.00 (0.931.09)

Myocardial infarction 413 (4.8) 440 (5.2) 438 (5.2) 1.07 (0.941.22) 1.08 (0.941.23)

Stroke 405 (4.7) 369 (4.3) 373 (4.4) 0.91 (0.791.05) 0.93 (0.811.07)

Hospitalization for heart failure 354 (4.1) 394 (4.6) 332 (3.9) 1.12 (0.971.29) 0.95 (0.821.10)

Death from cardiovascular causes 603 (7.0) 598 (7.0) 620 (7.3) 1.00 (0.891.12) 1.04 (0.931.17)

Death from noncardiovascular causes 411 (4.8) 391 (4.6) 445 (5.2) 0.96 (0.831.10) 1.10 (0.961.26)

Death from any cause 1014 (11.8) 989 (11.6) 1065 (12.5) 0.98 (0.901.07) 1.07 (0.981.16)

* Patients could have multiple events in this category. The numbers of events were 2058 (24.0%) in the ramipril group, 2042 (23.9%) in thetelmisartan group, and 2000 (23.5%) in the combination-therapy group. The differences were not significant (P = 0.83 for telmisartan vs.

ramipril, and P = 0.38 for combination therapy vs. ramipril). This composite was the primary outcome in the Heart Outcomes Prevention Evaluation (HOPE) trial.5

Patients could have multiple events in this category. The category includes both fatal and nonfatal events.

Table 4.Secondary and Other Outcomes.

OutcomeRamipril



Telmisartan vs.Ramipril

Combination Therapyvs. Ramipril

number (percent) relative risk (95% CI)

Revascularization 1269 (14.8) 1290 (15.1) 1303 (15.3) 1.03 (0.951.11) 1.04 (0.971.13)

Hospitalization for angina 925 (10.8) 954 (11.2) 952 (11.2) 1.04 (0.951.14) 1.04 (0.951.14)

Worsening or new angina 567 (6.6) 536 (6.3) 538 (6.3) 0.95 (0.841.07) 0.96 (0.851.08)New diagnosis of diabetes* 366 (6.7) 399 (7.5) 323 (6.1) 1.12 (0.971.29) 0.91 (0.781.06)

Any heart failure 514 (6.0) 537 (6.3) 478 (5.6) 1.05 (0.931.19) 0.94 (0.831.07)

New atrial fibrillation 570 (6.9) 550 (6.7) 537 (6.5) 0.97 (0.861.09) 0.96 (0.851.07)

Renal impairment 871 (10.2) 906 (10.6) 1148 (13.5) 1.04 (0.961.14) 1.33 (1.221.44)

Renal failure requiring dialysis 48 (0.6) 52 (0.6) 65 (0.8) 1.09 (0.741.61) 1.37 (0.941.98)

* The numbers of patients included in this analysis were 5427 in the ramipril group, 5294 in the telmisartan group, and 5280 in the combina-tion-therapy group.

This category includes only patients who did not have atrial fibrillation at baseline: 8296 in the ramipril group, 8259 in the telmisartangroup, and 8218 in the combination-therapy group.

No specific definitions were used. A determination of renal impairment was based on the clinical investigators report of an event that led tothe discontinuation of a study drug.

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which showed lower rates of cough and angio-edema in the valsartan group than in the capto-pril group but higher rates of hypotension-relatedsymptoms. There were more dose reductions (butnot discontinuations) because of renal complica-tions in the valsartan group than in the captoprilgroup, an association that was not observed in

our study.In order to establish noninferiority, a rigorous

trial design is required that includes a patientpopulation similar to that in the reference trial,a similar drug regimen, high adherence rates, out-comes that the comparator is known to affect, andhigh statistical power to exclude clinically impor-tant differences. All these criteria were satisfiedin our study. The entry criteria for our study andthe event rates in the ramipril group were simi-lar to those in the HOPE trial, with high follow-up rates in both trials. Moreover, the adherence

rate was higher in the ramipril group (89.4% at2 years and 84.7% at the end of the study amongpatients receiving either ramipril or an open-labelACE inhibitor) than that in the HOPE trial (85.0%and 78.8%, respectively). A sensitivity analysis thatwas restricted to patients who adhered to theirallocated drug regimen for more than 50% ofthe study period showed the consistency of ourresults and confirmed the robustness of nonin-feriority.

In our study, we confirmed the statisticalnoninferiority of telmisartan, as compared withramipril, since the upper boundary of the 97.5%confidence interval (1.09) was lower than thepredefined margin of 1.13 for both the primaryoutcome (P = 0.004) and the primary outcomeused in the HOPE trial (P = 0.001). Telmisartanpreserved about 95% (95% CI, 83.2 to 106.3) ofthe benefits of ramipril over placebo with respectto the primary outcome and preserved 105%(95% CI, 91.6 to 119.0) of the benefits with re-spect to the outcome of death from cardiovascu-lar causes, myocardial infarction, or stroke that

were observed in the HOPE trial. Use of the meth-od of Hasselblad and Kong21to impute effects oftelmisartan versus placebo (based on the bene-fits of ramipril over placebo in the HOPE trial)indicates a relative risk of 0.79 (95% CI, 0.70 to0.89) for the primary outcome. The number ofpatients who discontinued therapy was signifi-cantly smaller in the telmisartan group than inthe ramipril group, although the absolute differ-ence in the discontinuation rate was modest, be-

cause we used an active run-in phase that selectedpatients for randomization only if they toleratedboth medications. After randomization, we vig-orously reinforced adherence and encouraged pa-tients who stopped medications to restart them.In clinical practice, the rates of discontinuationmight be higher.

We also evaluated whether the combination oftelmisartan and ramipril (with both drugs target-ed to the full dose) would be superior to ramiprilalone. Surprisingly, despite a reduction in systolicblood pressure of 2 to 3 mm Hg in the combina-tion-therapy group, as compared with the ramiprilgroup a decrease that should have translatedinto a risk reduction of 4 to 5% no significantbenefit was seen in the primary outcome amongpatients receiving the two-drug therapy. However,combination therapy significantly increased therisk of hypotension, syncope, renal dysfunction,

and hyperkalemia, with a trend toward an in-creased risk of renal dysfunction requiring dialy-sis. These results are similar to the analysis of thecombined effects of an ARB and an ACE inhibi-tor, as compared with an ACE inhibitor alone, infour previous trials.22Therefore, even though com-bination therapy had a larger biologic effect (assuggested by greater blood-pressure lowering andchanges in potassium), dual blockade did not pro-duce any additional clinical benefit in this popu-lation.

In this regard, our results are also similar tothose of the VALIANT study, in which the com-bination of a full dose of captopril plus valsartan(the latter at a dose of 80 mg per day, which waslower than the 160 mg per day used in the val-sartan-only group) did not significantly reducethe occurrence of the primary outcome but didincrease hypotension.20Taken together, these twostudies showed no additive effect for an ARB inconjunction with a full dose of a proven ACE in-hibitor.

However, our findings contrast with those of

two other studies. In the Candesartan in HeartFailure: Assessment of Reduction in Mortality andMorbidity (CHARM) study,12which involved pa-tients who had symptomatic heart failure and hadbeen hospitalized in the previous 6 months, can-desartan, when added to existing therapy withany ACE inhibitor used at variable doses (with lessthan half the patients receiving full doses), wassuperior to placebo in reducing death or hospi-talization for heart failure. Similarly, a reduction



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0.7 1.0 1.3

Primary composite

Cardiovascular disease

Yes

NoSystolic blood pressure

134 mm Hg

>134 to 150 mm Hg

>150 mm Hg

Diabetes

Yes

No

HOPE risk score

3.677

>3.677 to 4.090

>4.090

Age

150 mm Hg

Diabetes

Yes

No

HOPE risk score

3.677

>3.677 to 4.090

>4.090

Age


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in hospitalization for heart failure was observedin the Valsartan Heart Failure Trial,11which com-pared valsartan with placebo in patients withheart failure, with about 90% of patients receiv-ing background therapy with ACE inhibitors atvariable doses. Both trials differed from both ourstudy and the VALIANT study in that decisionsregarding the dose and choice of an ACE inhibi-

tor were left to individual physicians, and therewas no attempt to titrate the ACE inhibitor to themaximum dose. Furthermore, patients had symp-tomatic heart failure despite receiving an ACE in-hibitor.

The lack of an additional benefit of a substan-tial lowering of blood pressure is puzzling, bothin our study and in the VALIANT study. Theseresults may have been due to previous successfultreatment of patients with other drugs so thatlittle further clinical benefit was possible withthe addition of full doses of multiple drugs thatblock the reninangiotensin system. Alternatively,some harm from combined therapy with ACE in-hibitors and ARBs used at full doses may offset

any potential gains. Further information is ex-pected regarding the role of ARBs as comparedwith placebo in patients after stroke,18in high-risk patients with vascular disease who are un-able to tolerate an ACE inhibitor,14 and in pa-tients with atrial fibrillation.19

In conclusion, our data show that in patients

who have vascular disease or high-risk diabetesbut do not have heart failure, telmisartan is anequally effective alternative to ramipril and is lesslikely to cause angioedema. The choice betweenthe two agents will depend on the preferences ofpatients and physicians and the individual patientssusceptibility to specif ic adverse events. There isno additional advantage (and there is some harm)from the combination of telmisartan and ramiprilused in full doses in this population, as comparedwith ramipril alone.

Supported by a grant from Boehringer Ingelheim, the Heart

and Stroke Foundation of Ontario, and a Senior ScientistAward from the Canadian Institutes of Health Research (to Dr.Yusuf).

Dr. Yusuf reports receiving consulting and lecture fees andresearch grants from Boehringer Ingelheim, AstraZeneca,Sanofi-Aventis, Servier, Bristol-Myers Squibb, and GlaxoSmith-Kline; Dr. Teo, receiving consulting and lecture fees and grantsupport from Boehringer Ingelheim; Dr. Schumacher, being anemployee of Boehringer Ingelheim; Dr. Dagenais, receivingconsulting and lecture fees from Boehringer Ingelheim andSanofi-Aventis and grant support from Sanofi-Aventis; Dr.Sleight, receiving consulting and lecture fees from BoehringerIngelheim and lecture fees from AstraZeneca and Sanofi-Aven-tis; and Dr. Anderson, receiving consulting fees from Boeh-ringer Ingelheim, Servier, Novo Nordisk, and AstraZeneca,lecture fees f rom Boehringer Ingelheim, Servier, AstraZeneca,and Sanofi-Aventis, and grant support from Boehringer Ingel-heim. No other potential conflict of interest relevant to thisarticle was reported.

We thank Judy Lindeman for her secretarial assistance.

Figure 3 (facing page).Relative Risks in PrespecifiedSubgroups.

Shown are the comparisons between the telmisartangroup and the ramipril group (Panel A) and between

the combination-therapy (telmisartan plus ramipril)

group and the ramipril group (Panel B). The risk scorefrom the Heart Outcomes Prevention Evaluation

(HOPE) trial5ranges from 2.350 to 5.928, with higherscores indicating higher risk. The sizes of the squares

are proportioned to the numbers of events.

Appendix

Current members of the Operations Committee are denoted by an asterisk. Previous members of the Operations Committee are de-noted by a dagger. NC denotes National Coordinator, and NL National Leader. Steering Committee:S. Yusuf (Chair and Principal In-vestigator),* P. Sleight,* C. Anderson,* K. Teo,* I. Copland,* B. Ramos, L. Richardson,* J. Murphy,* M. Haehl,* L. Hilbrich, R.Svaerd,* K. Martin, D. Murwin,* T. Meinicke, A. Schlosser,* G. Schmidt, R. Creek,* H. Schumacher,* M. Distel, B. Aubert, J.Pogue, L. Dyal, R. Schmieder, T. Unger, R. Asmar, G. Mancia, R. Diaz, E. Paolasso, L. Piegas, A. Avezum, G. Dagenais, E. CardonaMunoz, J. Probstfield, M. Weber, J. Young, R. Fagard, P. Jansky, J. Mallion, J. Mann, M. Bhm, B. Eber, N.B. Karatzas, M. Keltai, B.Trimarco, P. Verdecchia, A. Maggioni, F.W.A. Verheugt, N.J. Holwerda, L. Ceremuzynski, A. Budaj, R. Ferreira, I. Chazova, L. Rydn,T.L. Svendsen, K. Metsrinne, K. Dickstein, G. Fodor, P. Commerford, J. Redon, T.R. Luescher, A. Oto, A. Binbrek, A. Parkhomenko,

G. Jennings, L.S. Liu, C.M. Yu, A.L. Dans, R. Shah, J.-H. Kim, J.-H. Chen, S. Chaithiraphan. Data and Safety Monitoring Board:J. Cairns(Chair), L. Wilhelmsen, J. Chalmers, J. Wittes, M. Gent, C.H. Hennekens.Adjudication Committee:G. Dagenais (Chair), N. Anderson,A. Avezum, A. Budaj, G. Fodor, M. Keltai, A. Maggioni, J. Mann, A. Parkhomenko, K. Yusoff, P. Auger, V. Bernstein, E. Lonn, A.Panju, I. Anand, J.T. Bigger, P. Linz, J. Healey, C. Held, C. McGorrian, M. Rokoss, J. Villar. Substudies/Publication Committee:P.Sleight (Chair), C. Anderson, R. Creek, A. Dans, R. Diaz, R. Fagard, J. Probstfield, R. Svaerd, K. Teo, T. Unger, S. Yusuf. CoordinatingCenters:Hamilton K. Teo, I. Copland, B. Ramos, A. McDonald, J. Pogue, L. Dyal, R. Afzal, F. Zhao, S. Yusuf; Oxford P. Sleight, L.Richardson; Auckland C. Anderson, J. Murphy. Sites and Principal Investigators by Country:Argentina R. Diaz (NC), E. Paolasso(NL), R.A. Ahuad Guerrero, M. Amuchastegui, H.P. Baglivo, M. Bendersky, J. Bono, B. Bustos, A. Caccavo, L.R. Cartasegna, C.R. Cas-tellanos, M.A. Cipullo, P. Crunger, C.A. Cuneo, M. Focaccia, J.J. Fuselli, E. Hasbani, M.A. Hominal, J. Humphreys, F. Inserra, C.R.Killinger, E. Kuschnir, C.R. Majul, O.D. Manuale, G. Martinez, E.M. Marzetti, R. Nordaby, A.D. Orlandini, J.C. Pomposiello, G.M.Rodrguez, J. Salas, O.A. Salomone, R.A. Sanchez, C. Serra, M.L. Vico; Australia G.L.R. Jennings (NC), J.V. Amerena, L.F. Arnolda,G.M. Aroney, P.E. Aylward, C.F. Bladin, J.C. Bridgeman, B.R. Chambers, A.J. Corbett, D.S. Crimmins, D.B. Cross, L. Davies, S.M.



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Davis, G.A. Donnan, D.S. Eccleston, J.H. Frayne, R. Hendriks, G.K. Herkes, A.T. Hill, I.M. Jeffery, J.A. Karrasch, G. Koshy, T.H. Mar-wick, D.A. Owensby, M.W. Parsons, D.M. Rees, A. Russell, R. Schwartz, B. Singh, P.L. Thompson, J.H. Waites, W.F. Walsh, D.L.Walters, R.W. Watts, A.P. Whelan; Austria M. Bhm (NC), B.E. Eber (NL), J.B. Bonelli, P. Dolliner, J.H. Hohenecker, G.S. Steurer,W.W. Weihs; Belgium R. Fagard (NC), I. Bekaert, C. Brohet, P. Chaumont, P. Cheron, V. Crasset, J.-P. Degaute, P. Dendale, K. Du-jardin, S. Elshot, S. Hellemans, M. Herssens, G. Heyndrickx, P. Laloux, H. Lesseliers, P. Noyens, M. Quinonez, F. Stammen, H. Strie-kwold, J. Thoeng, W. Van Mieghem, G. Vanhooren, G. Vervoort, M. Vrolix, B. Wollaert; Brazil L. Piegas (NC), A. Avezum (NL), J.A.M. Abrantes, D. Armaganijan, J.C. Ayoub, L.C. Bodanese, A.C. Carvalho, M. Coutinho, J.P. Esteves, R.J.S. Franco, P.C.B.V. Jardim,J.F. Kerr Saraiva, P.E. Lees, L.N. Maia, J.A. Marin-Neto, R.L. Marino, D. Mion, Jr., J.R. Moreira, Jr., W. Oigman, R.C. Pedrosa, E.A.Pelloso, F.L. Plavnik, C.A. Polanczyk, . Rabelo, Jr., S. Rassi, G. Reis, A.B. Ribeiro, J.M. Ribeiro, J.C. Rocha, P.R.F. Rossi, R.D. Santos,

J.C.E. Tarastchuk, M.N. Villaln; Canada K. Teo (NC), G. Dagenais (NC), B. Abramson, M. Arnold, T. Ashton, P. Auger, I. Bata, K.Bayly, J. Beauchef, A. Blanger, V. Bernstein, R. Bhargava, A.W. Booth, S. Bose, M. Boulianne, M. Cameron, Y.K. Chan, C. Constance,P. Costi, D. Dion, J. Douketis, D. Fell, J.P. Giannoccaro, A. Glanz, G. Gosselin, D. Gould, S. Goulet, F. Grondin, M. Gupta, G. Gyenes,J.W. Heath, V.A. Heath, A. Hess, J.G. Hiscock, G. Hoag, G. Honos, J. Imrie, R. Kuritzky, C. Lai, A. Lalani, A. Lamy, P. LeBouthillier,H. Lochnan, E. Lonn, B. Lubelsky, A. Mackey, M. Meunier, A. Milot, L.B. Mitchell, S. Nawaz, M. Omichinski, A. Panju, C. Pilon, D.Pilon, P. Polasek, G. Proulx, T. Rebane, A.J. Ricci, D.W. Rupka, . Sabbah, D. Savard, N.K. Sharma, D. Shu, R. St. Hilaire, F. St. Mau-rice, R. Starra, B. Sussex, T. Szaky, P. Talbot, K.-W. Tan, T.B. To, S. Tobe, R. Tytus, R. Vexler, P. Whitsitt, V. Woo; China L. Liu (NC),X. Bai, X. Chen, J. Feng, S. Fu, Y. Ge, L. Gong, Z. He, J. Huang, Y. Jiang, L. Li, Q.H. Li, Y. Liao, Z. Lu, F. Lu, S. Ma, F. Niu, C. Pan, F. Qian,X. Shi, N. Sun, M. Sun, G. Sun, J. Wang, S. Wang, Y. Wang, Z. Wu, X. Yan, X. Yang, H. Yang, X. Ye, S. Yuan, T. Zhang, C. Zhang, F. Zhang,S. Zhang, D. Zhao, B. Zheng, H.Y. Zhou, S. Zhou, J. Zhu; Czech Republic P. Jansk (NC), V. Dedek, J. Dvork, R. Holaj, J. Kotou, E.Pederzoliov, M. Polk, J. Povoln, K. Smetana, J. pc; Denmark T.L. Svendsen (NC), L. Gtzsche, H.F. Juhl, K. Koelendorf, P. Lund, F.Pedersen, O.L. Perdersen, T. Pindborg, L.H. Rasmussen, S.L. Rasmussen, K. Thygesen, C. Tuxen; Finland K. Metsrinne (NL), R. Anti-kainen, M. Jskivi, I. Kantola, M. Kastarinen, P. Kohonen-Jalonen, A. Koistinen, E. Lehmus, R. Nuuttila, M.-L. Tuominen, H. Ylihrsil;France J. Mallion (NC), N. Abenhaim, J. Allix, L. Boucher, M. Bourgoin, A. Boye, N. Breton, D. Cadinot, A. Campagne, J. Churet, G.Constantin, E. De Sainte Lorette, A. El Sawy, G. Etchegarray, S. Farhat, F. Lacoin, T. Latte, C. Magnani, D. Pineau-Valenciennes, M. Pithon,A. Quguiner, J. Sicard, G. Sorbe, D. Taminau, H. Vilarem, J.Y. Vogel; Germany H.H. Ebert, S. Genth-Zotz, N. Hermanns, C. Holzer, J.

Minnich, D. Schimkus, M. Boehm (NC), J. Mann (NC), B. Brado, G. Claus, U. Dietz, R. Griebenow, T. Haak, K. Hahn, R. Hampel, H.Heitzer, G. Holle, T. Horacek, J. Jordan, C. Klein, R. Kolloch, S. Ludewig, W. Motz, T. Muenzel, H.P. Nast, M. Nauck, H. Nebelsieck, K.Rybak, H. Samer, T. Schaefer, J. Scholze, B. Schulze, Schleppinghoff, R. Schmieder, B. Schwaab, U. Sechtem, W. Sehnert, E. Steinhagen-Thiessen, G. Stenzel, P. Trenkwalder, B. Wedler, J. Zippel; Greece N. Karatzas (NC), A. Achimastos, E. Diamantopoulos, A. Efstratopou-los, M. Elisaf, H. Karvounis, D. Mentzikof, D. Mytas, D. Papadogiannis, V. Pyrgakis, C. Stefanadis, D. Symeonidis, A. Tsoukas, I. Vogiatzis,S. Voyaki, C. Zamboulis; Hong Kong C.-M. Yu (NC), C.K.H. Chan, L. Lam, Y.K. Lau, J. Sanderson, J. Wong, E.B. Wu, C.S. Yue; Hungary M. Keltai (NC), I. Czuriga, I. des, C.S. Farsang, . Kalina, K. Karlcai, K. Keltai, M. Kozma, Z. Lszl, V. Nagy, A. Papp, G.Y. Polk,I. Prda, A. Rnaszki, M. Sereg, K. Simon, S. Sonkodi, J. Szegedi, S. Timr, K. Tth, G.Y. Vndorfi, A. Vrtes; Ireland J. Feely, V.M.G.Maher, A.V. Stanton, P. Sullivan; Italy B. Trimarco (NC), P. Verdecchia (NC), A. Maggioni (NL), E. Agabiti Rosei, G.B. Ambrosio, M.Bentivoglio, A. Branzi, P. Cavallo Perin, M. Chiariello, V. Cirrincione, R. Ferrari, R. Gattobigio, E. Giovannini, D. Giugliano, A. Lacch, R.Lauro, G. Lembo, G. Marchetti, L. Moretti, L. Pancaldi, L. Partemi, S. Pede, G. Pettinati, G. Reboldi, R. Ricci, G. Rosiello, F. Rozza, M.G.Sardone, E.V. Scabbia, G. Selvetella, L. Tavazzi, P. Terrosu, A. Venco, A. Vetrano, M. Volpe, G. Zilio; Malaysia T. Ismail, R.P. Shah, M.Singaraveloo, W.A. Wan Ahmad, Z. Yusof, K. Yusoff, I. Zainal Abidin, R. Zambahari; Mexico E. Cardona Munoz (NC), L. Alcocer Diaz,S. Pascoe-Gonzalez, R. Arriaga Nava, G. De La Pea Topete, L.A. Elizondo Sifuentes, H.R. Hernndez Garca, J. Illescas-Diaz, M.A. MacasIslas, J.A. Noriega Arellano, R. Olvera Ruiz, J.Z. Parra Carrillo, G. Velasco Snchez, M. Vidrio Velsquez; the Netherlands F.W.A. Verheugt(NC), N.J. Holwerda (NL), D.C.G. Basart, A.J.M. Boermans, H.A. Bosker, K.P. Bouter, C.P. Buiks, W.A. de Backer, J. J. de Graaf, J.H.M.

Deppenbroek, F.D. Eefting, F.C.N.M. Gunneweg, H.R. Michels, D. Poldermans, G. Schrijver, M.I. Sedney, T. Slagboom, J.G. Smilde,G.E.M.G. Storms, R.M. Tjon, P.F.M.M. van Bergen, G.J.M. van Doesburg, L.H.J. van Kempen, H.F.C.M. van Mierlo, A. Veerman, F.A.A.M.Vermetten, A. Wester; New Zealand W. Bagg, J. Benatar, R.J. Coxon, R.N. Doughty, D.H. Friedlander, R.A. Luke, P.L. Nairn, Y. Ratnasa-bapathy, A.M. Richards, G.P. Singh, R.A.H. Stewart, R.W. Troughton, H.D. White, M. Williams, S.P. Wong; Norway K. Dickstein (NL),N. Bogale, J.O. Lier, J.E. Otterstad, P.K. Rnnevik, S. Skeie, P.O. Walle; Philippines A.L. Dans (NC), M.T.B. Abola, J.C. Aonuevo, J.M.Jaro, D.R. Maraon, V.L. Mendoza, D.R. Morales, E.P. Pacheco, E.B. Reyes, A.A. Roxas, M.B. Sedurante; Poland L. Ceremuzynski (NC),A. Budaj (NC), Z. Binio, M. Bronisz, P. Buszman, T. Czerski, M. Dalkowski, J. Gessek, A. Gieroba, K. Janik, M. Janion, T. Kawka-Urbanek,R. Klabisz, M. Krauze-Wielicka, S. Malinowski, P. Miekus, J. Mormul, M. Ogorek, G. Opolski, M. Skura, M. Szpajer, M. Tendera, T.Waszyrowski, M. Wierzchowiecki, B. Zalska; Portugal R. Ferreira (NC), R. Capucho, C. Correia, L. Cunha, J.M. Ferro, V. Gama Ribeiro,V. Gil, P. Marques da Silva, M. Oliveira Carrageta, R. Sebra Gomes, M. Veloso Gomes; Russia I. Chazova (NC), F. Ageev, Y. Belenkov,A. Ivleva, Y. Karpov, M. Shestakova, E. Shlyakhto, S. Shustov, B. Sidorenko; Singapore H.M. Chang, B. Kwok; Slovakia G. Fodor (NC),A. Dukt, J. Gonsorck, M. Hranai, J. Lietava, D. Pella, R. Rybar, L. Ruffini; South Africa P. Commerford (NC), F. Bonnici, B. Brown, A.J.Dalby, G.J. Gibson, L. Herbst, J. King, E. Klug, M. Middle, D. P. Naidoo, M. Pretorius, G. Podgorski, N. Ranjith, K. Silwa-Hahnle, H.Theron; South Korea J.H. Kim (NC), S.C. Chae, N.S. Chung, K.P. Hong, M.H. Jeong, H.J. Kang, J.J. Kim, M.H. Kim, H.S. Seo, E.K. Shin;Spain J. Redn (NC), J. Abelln, P. Aranda, V. Barrios, C. Calvo, M. De La Figuera, E. De Teresa, R. Dur, F. Escobar, F. Fernandez-Cruz,E. Galve, J. Garcia-Puig, B. Gil-Extremera, R. Gomis, O. Gonzalez-Albarran, J.R. Gonzlez-Juanatey, A. Llacer, L. Lpez-Bescs, J. Olivn,A. Pic, A. Pose, A. Roca-Cusachs, L.M. Ruilope; Sweden L. Rydn (NC), A. Alvng, P.-. Bostrm, M. Dellborg, U.-B. Ericsson, J. Her-litz, T. Juhlin, K. Pedersen, B. Strng, B. Sundqvist, B.-O. Tengmark, G. Ulvenstam, B. Westerdahl, L. Winberg; Switzerland T.R. Luescher(NC), I. Baumgartner, P. Dubach, A. Gallino, T. Moccetti, G. Noll, A. Nordmann, H. Rickli, H. Schlpfer, K. Weber; Taiwan J.-H. Chen(NC), T.H. Chao, C.Y. Chen, J.J. Cheng, H.C. Chiou, C.C. Fu, M. Fu, W.T. Lai, Y.H. Li, L.M. Lien, C.D. Tsai, J.H. Wang, P.S. Yeh; Thailand S. Chaithiraphan (NC), T. Chantadansuwan, K. Jirasirirojanakorn, R. Krittayaphong, P. Laothavorn, N. Mahanonda, S. Sitthisook, S.Tanomsup, S. Tansuphaswadikul, P. Tatsanavivat, S. Yamwong; Turkey A. Oto (NC), M. Akin, N.T. Caglar, A. Ergin, H. Mderrisoglu,A. Oguz, Z. Ongen, V. Sansoy, T. Tetiker, A. Uysal; Ukraine A. Parkhomenko (NC), E. Amosova, O. Cherkasova, Y. Dykun, G. Dzyak, A.Galystska, O. Grishyna, O. Jaremenko, L. Kononenko, E. Koval, V. Kovalenko, V. Netyazhenko, T. Pertseva, A. Prokhorov, G. Radchenko,Y.U. Rudyk, Y. Sirenko, A. Skarzhevsky; United Arab Emirates A.S. Binbrek (NC), A.A.R. Al Hajiri, E. Al Hatou, A.A.S. Al-Sousi, M. Alo-mairi, I. Maqsood Wajib; United Kingdom P. Sleight (NC), A.A.J. Adgey, R. Andrews, S.G. Ball, D.H. Barer, A.H. Barnett, A.B. Bridges,V. Bryson, A.S. Cowie, A.J. De Belder, R. Donnelly, C.M. Francis, J. Furnace, S.K. Glen, N. Gough, A.M. Heagerty, P.R. Jackson, S.H.D.Jackson, E. Joyce, D.J. McEneaney, A.J. Moriarty, D.L. Murdoch, J.P. OHare, W.J. Penny, C.J. Reid, J. Tilley, J.P. Vora, J. Webster, B. Wil-



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liams; United States J. Probstfield (NC), M. Weber (NC), J. Young (NC), I. Ahmed, I.S. Anand, J.L. Anderson, J.S. Aponte Pagn, J. Barzilay,J.N. Basile, P.F. Bass III, S.S. Blumenthal, W.J. Bommer, D.F. Brautigam, C.D. Brown, N. Brown, J.D. Byrum, A.A. Carr, J. Chinn, D. Chiu,N.R. Cho, J.O. Ciocon, P.J. Coln-Ortz, J.B. Cruz, W.D. Dachman, G.M. Dolson, S.G. Dorfman, W. Drummond, C. East, F. Eelani, H.S.Ellison, J.V. Felicetta, M.H. Fishbach, R.W. Force, S.J. Giddings, M.C. Goldberg, S. Goldman, R. Gomez Adrover, S.L. Goss, S.P. Graham,C.B. Granger, M.M. Greenspan, R.H. Grimm, G.B. Habib, M.R. Hagen, P.D. Hart, T.J. Hartney, M.A. Henriquez, J.J. Holland, B.J. Hoog-werf, M. Hossfeld, A.K. Jacobson, M.J. Jelley, T.V. Jones, R.A. Kaplan, D.G. Karalis, L.A. Katz, D.J. Kereiakes, M. Khan, R.M. Kipperman,M.J. Kozinn, J.G. Kozlowski, E.W. Lader, C. Landau, J.S. Landzberg, D. Laughrun, S.J. Lewis, C.S. Liang, M.C. Limacher, P.E. Linz, T.S.Lo, F. Lopez-Arostegui, R.R. Maddox, P.R. Mahrer, M.S. Maurer, D.K. McGuire, A.D. Mercando, J.H. Mersey, M. Meyer, A.N. Mooss, P.Narayan, S. Oparil, D.N. Padhiar, A.L. Phillips, M. Prisant, N. Qureshi, M.P. Raghuwanshi, R.R. Randall, T.M. Retta, R.E. Ringrose, A.A.

Rizvi, M.D. Rizvi, M.G. Saklayen, S. Sastrasinh, I.K. Savani, A. Schlau, H.S. Schultz, M.J. Schweiger, R.D. Smith, M. Sosa-Padilla, D.Streja, T.P. Stuver, D.C. Subich, F.C. Sulak, W.A. Swagler III, M. Taitano, J.A. Tavarez-Valle, E.M. Taylor, M.L. Tuck, W.B. White, W.J.Wickemeyer, T.B. Wiegmann, P.A. Zee, X.Q. Zhao.

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